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Genome-wide association studies implicate variations in  CHRNA5  and  CHRNA3  as being associated with nicotine addiction (NA). Multiple common haplotypes (“risk”, “mixed” and “protective”) exist in Europeans; however, high linkage disequilibrium between variations in  CHRNA5  and  CHRNA3  makes assigning causative allele(s) for NA difficult through genotyping experiments alone. We investigated whether  CHRNA5  or  CHRNA3  promoter haplotypes, associated previously with NA, might influence allelic expression levels. For  in vitro  analyses, promoter haplotypes were sub-cloned into a luciferase reporter vector. When assessed in BE(2)-C cells, luciferase expression was equivalent among  CHRNA3  haplotypes, but the combination of deletion at rs3841324 and variation at rs503464 decreased  CHRNA5  promoter-derived luciferase activity, possibly due to loss of an SP-1 and other site(s). Variation within the  CHRNA5  5’UTR at rs55853698 and rs55781567 also altered luciferase expression in BE(2)-C cells. Allelic expression imbalance (AEI) from the “risk” or “protective” haplotypes was assessed in post-mortem brain tissue from individuals heterozygous at coding polymorphisms in  CHRNA3  (rs1051730) or  CHRNA5  (rs16969968). In most cases, equivalent allelic expression was observed; however, one individual showed  CHRNA5  AEI that favored the “protective” allele and that was concordant with heterozygosity at polymorphisms ∼13.5 kb upstream of the  CHRNA5  transcription start site. Putative enhancer activity from these distal promoter elements was assessed using heterologous promoter constructs. We observed no differences in promoter activity from the two distal promoter haplotypes examined, but found that the distal promoter region strongly repressed transcription. We conclude that  CHRNA5  promoter variants may affect relative risk for NA in some heterozygous individuals.

In Vitro and Ex Vivo Analysis of CHRNA3 and CHRNA5 Haplotype Expression